4-alkoxy-pyrido[2,3-d]pyrimidine derivatives for treatment of myocardiac ischemia

ABSTRACT

4-Alkoxy-pyrido[2,3-d]pyrimidine derivatives are described as well as processes for their preparation. 
     For reason of their vasospasmolytic effects these compounds are mainly indicated for the treatment of cerebral, cardiac, and peripheral vascular diseases such as myocardiac ischemia, cerebral infarction, pulmonary thromboses, as well as in cases of arterioschlerosis and other stenotic disorders. They are therefore valuable agents for combating cardiovascular mortality.

This is divisional application of U.S. Ser. No. 787,844 filed Oct. 16,1985, now U.S. Pat. No. 4,681,882.

SUMMARY OF THE INVENTION

The invention concerns new 4-alkoxy-pyrido[2,3-d]pyrimidine derivativesof the general Formula I ##STR1## wherein R¹ represents an unsubstitutedor substituted aromatic or heteroaromatic ring;

R² represents a nitrile group, a carboxyl group or an alkoxycarbonylresidue with up to six carbon atoms;

R³ is a straight-chained or branched alkyl group with up to four carbonatoms or an amino group; and

R⁴ represents a straight-chained or branched alkyl group with up to fourcarbon atoms;

as well as optionally the pharmaceutically acceptable salts thereof.

Another subject matter of the present invention is the use of4-alkoxy-pyrido[2,3]pyrimidine derivatives of the general Formula I forthe treatment of vascular diseases and pharmaceutical compositionscontaining the new compounds.

DETAILED DESCRIPTION

The compounds of the present invention may be prepared by a processcharacterized in that 4-oxopyrido[2,3-d]pyrimidine derivatives of thegeneral Formula III. ##STR2## wherein R¹ and R³ have the above meaning,and R² ' represents a nitrile group or an alkoxycarbonyl residue with upto six carbon atoms, is 0-alkylated in a generally known manner.

The compounds of the general Formula III serving as the startingproducts are prepared by either:

(a) reacting a dihydropyridine of the general Formula IV ##STR3##wherein R¹, R² ', R³, and R⁵ have the above meaning, with s-triazine inthe presence of a base, or

(b) condensing a compound of the general Formula V ##STR4## wherein R¹and R² ' have the above meaning, and R³ ' represents a straight-chainedor branched alkyl group with up to four carbon atoms, by heating in apolar solvent with 6-amino-4-hydroxypyrimidine.

Compounds of the general Formula I, in which R² represents a carboxylgroup, are prepared by hydrolyzing compounds of the general Formula I,in which R² represents an alkoxycarbonyl residue suitable for thesplitting of esters, in a generally known manner, preferably in an acidmedium.

The compounds of the general Formula IV (cf. e.g., "Liebig's Ann. Chem."1977, p. 1895, or "Arzneim. Forsch." 31 (II), 8 (1981), p. 1173) and V(cf. e.g., "Arch. Pharm." 317 (1984), p 709) are known from theliterature and can be prepared in an analogous manner.

In order to perform reaction (a) the dihydropyridine derivative isheated to temperatures between 50 and 160° C., preferably 100°-150° C.,together with s-triazine in an inert organic solvent in the presence ofstrong bases such as, e.g., alkali alcoholates or sodium hydride in aninert organic solvent. Suitable solvents are mainly polar solvents suchas dimethylsulfoxide, dimathylformamide or ethyleneglycol dimethylether.

This reaction produces, in addition to the compounds of the generalFormula III isolated as the main products, also compounds according toGerman Offenlegungschrift No. 33 27 650, which are separated bychromatography.

The reaction (b) is performed by heating the two components in an acidmedium, preferably in boiling glacial acetic acid.

Pursuant to the invention the 4-alkoxy-pyrido[2,3-d]pyrimidinederivatives of the general Formula I are prepared according to the usualprocesses as described for the O-alkylation of lactams in the literature(cf. "Adv. Heterocyclic Chem." 12 (1970), 185-212). Suitable alkylationagents are alkyl halides and alkyl sulfonates, dialkyl sulfates andtrialkyl oxonium salts.

For the reaction with alkyl halides the compounds of the general FormulaIII are used in the form of their metallic salts, preferably theiralkali salts or silver salts, which are either prepared separately or insitu by means of suitable bases such as metallic hydrides, carbonates oralkoxides in an aprotic solvent. Dependent on the alkylation agent usedsutable solvents are almost all inert organic solvents such asopen-chained, cyclic or aromatic hydrocarbons, e.g., n-pentane,n-hexane, cyclohexane, benzene, or toluene, halogenated hydrocarbonssuch as dichloromethane and 1,2-dichloroethane, ether, such as, e.g.,diethylether and 1,2-dimethoxyethane, as well as dipolar aproticsolvents such as dimethylformamide, hexamethylphosphoric acid triamideand dimethylsulfoxide. Dependent on the solvent used the temperature mayvary between -20° C and the boiling point of the respective solvent.

For reason of the ambident character of the lactam anion, and dependenton the reaction conditions and alkylation agents used, the alkylationoften yields mixtures of O-alkylation and N-alkylation products ("J.Org. Chem." 32 (1967), 4040 ff).

The product mixtures thus obtained may be separated by means ofchromatography and/or crystallization.

The 4-alkoxy-pyrido[2,3-d]pyrimidine derivatives of the general FormulaI are obtained preferably by reacting the 4-oxo-pyrido[2,3-d]pyrimidinesof the general Formula III with trialkyl oxonium salts, in particulartrimethyloxoniumtetrafluoroborate, in an aprotic solvent. TheO-isopropyl compounds, on the other hand, are advantageously obtained byalkylation of the alkali metallic salts with isopropyl halides

Since the compounds of the general Formula I according to the inventionhave a chiral center at C-5 they may be present either as racemicmixtures, or in the form of the enantiomers.

The pharmaceutically acceptable salts are obtained in the usual mannerby neutralization of the bases with corresponding inorganic or organicacids. As acids may be used, e.g., hydrochloric acid, sulfuric acid,phosphoric acid, lactic acid, citric acid, malic acid, salicyclic acid,ascorbic acid, malonic acid, or succinic acid.

By unsubstituted or substituted aromatic or heteroaromatic ring, thereis meant phenyl or phenyl substituted by up to three of the same ordifferent groups selected from a straight or branched alkyl with up tofour carbon atoms, halogen selected from fluorine, chlorine, bromine oriodine, nitro, a straight or branched alkoxy with up to four carbonatoms, difluoromethoxy, trifluoromethoxy, dialkylamino in which alkyl isas defined above, alkylthio in which alkyl is as defined above ortrifluoromethyl, or a methylenedioxy group; or a pyridyl, e.g., 2-, 3-,or 4-pyridyl, or thienyl group (2- or 3-) which is unsubstituted orsubstituted by alkyl as defined above.

Preferred are compounds of the general Formula I wherein:

R¹ represents an unsubstituted or substituted phenyl residuesubstituted, preferably in two or three position, by halogen, nitro,methyl, methoxy, difluoromethoxy, trifluoromethoxy, dimethylamino ordiethylamino, methylthio or trifluoromethyl, or a phenyl residuedisubstituted, preferably in 2,3 position by methoxy or methylenedioxy,or in 2,3 or 2,6 position by halogen atoms, which may be the same ordifferent;

R² represents a nitrile group, a carboxyl group or an alkoxycarbonylresidue, in particular a methoxy, ethoxy, isopropoxy, isobutoxy, ormethoxyethoxy carbonyl residue;

R³ represents a methyl or ethyl residue or an amino group;

R⁴ represents a methyl, ethyl, n-propyl or isopropyl residue.

The compounds of the general Formula I possess valuable pharmacologicalproperties. In particular they produce calcium-antagonistic effects suchas, e.g., termination of smooth-muscle contraction from potassiumdepolarization induced by calcium.

For reason of their vasospasmolytic effects the compounds are mainlyindicated for the treatment of cerebral, cardiac, and peripheralvascular diseases such as myocardiac ischemia, cerebral infarction,pulmonary thromboses, as well as in cases of arteriosclerosis and otherstenotic disorders. The 4-alkoxypyrido[2,3-d]pyrimidine derivatives ofthe present invention are therefore valuable agents for combatingcardiovascular mortality. Another subject-matter of the presentinvention is therefore the use of 4-alkoxypyrido[2,3-d]pyrimidinederivatives of the general Formula I in the treatment of vasculardiseases.

The compounds of the general Formula II according to the invention maybe applied in liquid or solid form, orally or parenterally. For thesolution for injection mainly water is used containing such additives asstabilizers, solubilizers or buffers as are usual for solutions forinjection.

Such additives are, e.g., tartrate and citrate buffers, ethanol, complexformers (such as ethylenediamine-tetraacetic acid and the nontoxic saltsthereof) as well as high molecular weight polymers (such as liquidpolyethylene oxide) to regulate viscosity. Solid vehicles are, e.g.,starch, lactose, mannitol, methyl cellulose, talcum, highly dispersedsilicic acid, high molecular weight fatty acids (such as stearic acid),gelatin, agar-agar, calcium phohsphate, magnesium stearate, animal andvegetable fats, solid high molecular weight polymers (such aspolyethylene glycol); if desired preparations for oral application mayin addition contain flavors and/ or sweetening agents.

The enterally administered single doses are in the order from about 5 to250 mg, preferably 10-100 mg. Doses for parenteral application would bein the order from about 1 to 20 mg.

The following examples serve to illustrate the invention further.

EXAMPLE 1 (±)-5,8-Dihydro-4-isopropoxy-7-methyl-5-phenyl-pyrido[2,3-d]-pyrimidine-6-carboxylic acid ethyl ester

To a stirred suspension of 1.0 g (34 mmol) sodium hydride (80% in liquidparaffin) in 60 ml dimethylformamide is added dropwise a solution of 6.5g (21 mmol)(±)-3,4,5,8-tetrahydro-7-methyl-4-oxo-5-phenyl-pyrido[2,3-d]pyrimidine-6-carboxylicacid ethyl ester in 60 ml dimethylformamide. When the gas generationdiminishes stirring is continued at room temperature for 30 minutes;subsequently 5.1 g (30 mmol) isopropyl iodide in 15 ml dimethylformamide are added dropwise.

Stirring is continued at room temperature for 20 hours, the solventevaporated under vacuum, and the residue mixed with 100 ml water bystirring. The crystals forming are filtered off, dried, dissolved inacetic acid ethyl ester, and subjected to chromatography on silica gelwith toluene/acetic acid ethyl ester 1:1.

The fraction of the R_(f) 0.5 is isolated and recrystallized fromdiisopropylether/ethanol. This process yields(±)-5,8-dihydro-4-isopropoxy-7-methyl-5-phenyl-pyrido[2,3-d]pyrimidine-6-carboxylicacid ethyl ester in the form of colorless crystals with a mp of201°-202° C.

The(±)-3,4,5,8-tetrahydro-7-methyl-4-oxo-5-phenyl-pyrido[2,3-d]pyrimidine-6-carboxylicacid ethyl ester used as the starting material is prepared as follows:

(±)-3,4,5,8-Tetrahydro-7-methyl-4-oxo-5-phenylpyrido[2,3-d]pyrimidine-6-carboxylicacid ethyl ester (process a)

To a stirred suspension of 4.5 g (150 mmol) sodium hydride (80% inliquid paraffin) in 75 ml dimethylformamide is added dropwise, and innitrogen atmosphere, a solution of 40.6 g (123 mmol)(±)-2-amino-1,4-dihydro-6-methyl-4-phenylpyridine-3,5dicarboxylic aciddiethyl ester in 200 ml dimethylformamide. When the gas generationdiminishes stirring is continued at room temperature for 30 minutes;subsequently 10.0 g (123 mmol) s-triazine in 250 ml dimethylformamideare added dropwise. The reaction mixture is heated to 110° C. for 16hours and reduced under vacuum when cool. The dark residue is subjectedto chromatography on silica gel with dichloromethane/ethanol 95:5. Thefraction of the R_(f) 0.5 is isolated, heated to boiling with acetone,and the crystals precipitated after cooling are recrystallized fromethanol for the purpose of further purification.

This process yields(±)-3,4,5,8-tetrahydro-7-methyl-4-oxo-5-phenyl-pyrido[2,3-d]pyrimidine-6carboxylicacid ethyl ester in the form of being crystals with a m.p. of 303°-305°C. (deconposition).

Analogously the following compounds are obtained.

(±)-5-(2-Fluorophenyl)-5,8-dihydro-4-isopropoxy-7-methyl-pyrido[2,3-d]pyrimidine-6-carboxylicacid ethyl ester (1.a)

m.p. 186°-187° C. from diisopropyl ethyl/ethanol.

(±)-5,8-Dihydro-4-isopropoxy-7-methyl-5-(3-nitrophenyl)pyrido[2,3-d]pyrimidine-6-carboxylicacid- (2-methoxy)ethyl ester (1.b)

m.p. 170°-172° C. from diisopropyl ether/isopropanol.

(±)-5,8-Dihydro-4-isopropoxY-7-methyl-5-(2-trifluromethylphenyl)pyrido[2,3-d]pyrimidine-6-carboxylicacid methyl ester (1.c)

m.p. 214°-215° C. from diisopropyl ether/methanol.

(±)-5,8)Dihydro-4-isopropoxy-7-methyl-5-(3-nitrophenyl)pyrido[2,3-d]pyrimidine-6-carboxylicacid isopropyl ester (1.d)

m.p. 181°-182° C. from diisopropyl ether/isopropanol.

(±)-7-Amino-5,8-dihydro-4-isopropoxy-5-(2-methoxyphenyl)pyrido[2,3-d]pyrimidine-6-carboxylicacid ethyl ester (1.e)

m.p. 222°-223° C. from diisopropyl ether/acetic acid ethyl ester.

(±)-5,8-Dihydro-4-isopropoxy-7-methyl-5-(2-trifluoromethylphenyl)pyrido[2,3-d]pyrimidine-6-carboxylicacid ethyl ester (1.f)

m.p. 155° C. from diisopropyl ether.

(±)-5,8-Dihydro-4-isopropoxy-7-methyl-5-(3-nitrophenyl)pyrido[2,3-d]pyrmidine-6-carboxylicacid methyl ester (1.g)

m.p. 218°-219° C. from diisopropyl ether/methanol.

EXAMPLE 2(±)-5,8-Dihydro-4-methoxy-7-methyl-5-(3-nitrophenyl)pyrido[2,3-d]pyrimidine-6-carboxylicacid isopropyl ester

Three and 0.7 g (10 mmol)(±)-3,4,5,8-tetrahydro-7-methyl-5-(3-nitrophenyl)-4-oxo-pyrido[2,3-d]-pyrimidine-6-carboxylicacid isopropyl ester and 3.0 g (20 mmol)trimethyloxonium-tetrafluoroborate are stirred in 150 ml1,2-dichloroethane in nitrogen atmosphere and at room temperature forthree hours. The product is extracted twice with 50 ml saturated sodiumhydrogen carbonate solution, the organic phase is separated, dried oversodium sulfate and reduced under vacuum. Twice recrystallizing theresidue from diisopropyl ether/isopropanol yields the product in theform of colorless crystals with a mp of 212°-213° C.

The following comparison studies with isolated muscles serve toillustrate the pharmacological efficacy of the compounds according tothe general Formula 1.

Isolated Smooth Muscles (Table 1)

Of rabbits (vessel ring segments of arteria basilaris and a. coronariaare mounted in an organ bath in a way to allow the measurement ofisometric contractions. Contractile activity is elicited by a potassiumdepolarization in Tyrode's solution. This experimental set-up is awell-known standard model for the identification of substances blockingthe calcium channels opened during the potassium depolarization(Fleckenstein, Calcium Antagonism in Heart and Smooth Muscle, J. Wiley &Sons, 1983).

                  TABLE 1                                                         ______________________________________                                        Concentrations (IC.sub.50, mol/l) of compounds effecting a                    semimaximal inhibition of the K.sup.+-  depolarization contraction of         vessel rings in the organ bath. A.bas. = arteria basilaris,                   a cor. = arteria coronaria of the rabbit; mean diameter 0.5-1.0 mm.           Example                                                                       Number        a. basilaris                                                                            a. coronaria                                          ______________________________________                                        1b            3.9 × 10.sup.-8                                                                   3.4 × 10.sup.-8                                 1c              4 × 10.sup.-8                                                                   4.5 × 10.sup.-8                                 1d            3.3 × 10.sup.-8                                                                   1.6 × 10.sup.-7                                 1e            2.8 × 10.sup.-6                                                                   7.3 × 10.sup.-8                                 1f            3.8 × 10.sup.-8                                                                   3.4 × 10.sup.-8                                 1g            2.8 × 10.sup.-8                                                                   2.3 × 10.sup.-7                                 2             2.5 × 10.sup.-9                                                                   1.4 × 10.sup.-7                                 ______________________________________                                    

We claim:
 1. A metod for treating myocardiac ischemia which comprisesadministering to a host suffering therefrom a pharmaceutical compositionin unit dosage form comprising a calcium antagonist effective amount ofa compound of the formula ##STR5## wherein R¹ is phenyl, pyridyl orthienyl, or phenyl substituted by up to three of the same or differentgroups selected from a straight or branched alkyl with up to four carbonatoms, halogen, nitro, a straight or branched alkoxy with up to fourcarbon atoms, difluoromethoxy, trifluromethoxy, diloweralkylamino,loweralklthio or trifluoromethyl or a methylenedioxy group; R²represents a nitrile group, a carboxyl group or an alkoxycarbonylresidue with up to six carbon atoms; R³ is a straight-chained orbranched alkyl group with up to four carbon atoms or an amino group; andR⁴ represents a straight-chained or branched alkyl group with up to fourcarbon atoms; or a pharmaceutically acceptable salt thereof with apharmaceutically acceptable carrier in diluent.